D-mannitol and its preparation

ABSTRACT

D-mannitol having a specific surface area of not less than about 1 m2/g is disclosed. The D-mannitol shows improved compressibility and is useful as an excipient.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a novel D-mannitol and its preparation.More specifically, it relates to D-mannitol which can be used as anexcipient with excellent compressibility in the fields of preparation ofmedicaments and food processing industry, and a process for preparingit.

2. Description of the Related Art

D-mannitol is excellent in safety and in its compatibility withphysiologically active substances. And, since it is not hygroscopic andretains no substantial moisture, it is of high value as an excipient forformulation of, especially, a physiologically active substance of highmoisture sensitivity into tablets or capsules. On the other hand,D-mannitol is poor in bindability when subjected to compression and,besides, its friction with a metal wall is strong. These shortcomingstend to cause die friction or capping upon compression, which fails togive sufficient hardness to the aimed tablets, giving wear on the wallof a die and on the side face of a punch, even making sometimes therunning of a tabletting machine difficult. In view of the foregoing, useof D-mannitol as excipient has been restricted in very limited dosageforms such as chewable tablets.

D-mannitol is crystalline powder having polymorphic forms classifiedinto α form, β form and δ form by X-ray diffraction patterns[Walter-Levy, L., Acad. Sc. Paris, t. 267 Series C, 1779 (1968)]. Forimproving the compressibility of crystalline powder, it has been knownthat, in general, crystals are finely ground to increase the bindingpoints to give a better compressibility. However, in the case ofD-mannitol, mere grounding of it into fine powder enhances the frictionwith the metal wall when subjected to compression, and also involvesproblems on its handling such as dusting and lowering of fluidity.

And, in Journal of Pharmaceutical Sciences, 53 (2), 188-192 (1964),there is a report on a method of obtaining D-mannitol improved in itscompressibility, which comprises fusing D-mannitol and, immediatelycooling. However, the improvement in compressibility brought by thismethod is not the one sufficiently meeting the requirements in theformulation process. Besides, the procedure is specific, so that it isdifficult to apply to a industrial production scale, leaving a problemfrom the viewpoint of cost.

One object of the present invention is to provide D-mannitol by a simpleprocedure, which is excellent in powder properties and dramaticallyimproved in compressibility.

Another object of the present invention is to provide a process forpreparing D-mannitol.

Still another object of the present invention is to provide a solidcomposition comprising D-mannitol as an excipient.

These objects as well as other objects and advantages of the presentinvention will be apparent to those skilled in the art from thefollowing description with reference to the accompanying drawings.

SUMMARY OF THE INVENTION

Under these circumstances, the present inventors have studiedintensively to establish a process for preparing D-mannitol excellent inpowder properties and improved in compressibility, by a simpleprocedure. As a result, it has been found that, when δ form crystals arebrought into contact with a water-soluble solvent, they are transformedinto β form at the contact interface to give fine crystallineprecipitates. This phenomenon has suggested to the present inventorsthat D-mannitol composed of an aggregation of fine crystals could beobtained. The present invention has been completed by the presentinventor's further intensive investigation of based on this suggestion.

That is, according to the present invention, there is providedD-mannitol having a specific surface area of not less than about 1 m²/g,in particular, such D-mannitol comprising a mixture of δ form crystalsand β form crystals.

In another aspect, the present invention provides a process forpreparing D-mannitol having a specific surface area of not less thanabout 1 m²/g which comprises treating δ form D-mannitol crystals with awater-soluble solvent, followed by drying. In this aspect, it ispreferred to use the water-soluble solvent in an amount of about 3 toabout 70 W/W % based on the weight of the δ form D-mannitol crystals.

In still another aspect, the present invention provides a solidcomposition comprising D-mannitol having a specific surface area of notless than about 1 m²/g. Preferably, the solid composition of the presentinvention further comprises a pharmacologically active component, forexample, a highly moisture-sensitive component, in particular, sodium3R,5S-(+)-erythro-(E)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-methoxymethyl-pyrid-3-yl]-3,5-dihydroxy-hept-6-enoate.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph illustrating the hardness of the compressed productsprepared in Example 1 and that of the compressed product prepared inComparative Example 1 hereinafter. In FIG. 1, the open circle and theopen square respectively show the comparative compressed products usinguntreated δ form crystals and β form crystals, while the closed circleand the closed square respectively show the results observed in thecompressed product prepared by using treated crystals of Example 1 andComparative Example 1.

FIG. 2 is the scanning electron microscopic image of the D-mannitol ofthe present invention prepared in Example 1.

FIG. 3 is the scanning electron microscopic image of the δ formcrystals.

FIG. 4 is the respective powder X-ray diffraction patterns of theD-mannitol of the present invention and δ form and β form D-mannitol.

FIG. 5 is the respective hardness of the compressed product prepared inExample 2 and that of the compressed product prepared in ComparativeExample 2 hereinafter.

FIG. 6 is a graph illustrating the respective hardness of the compressedproduct of Example 3 and that of the compressed product of ComparativeExample 3 hereinafter.

FIG. 7 is a graph illustrating the respective strength of the compressedproduct of Example 4 and that of the compressed product of ComparativeExample 4.

FIG. 8 is a graph illustrating the relation of the amount of purifiedwater used for treatment of the δ form crystals with the properties ofthe resultant D-mannitol.

DESCRIPTION OF THE PREFERRED EMBODIMENT

The D-mannitol of the present invention is the β form crystals alone ora mixture thereof with the δ form crystals, which is an aggregate ofD-mannitol crystals whose specific surface area is not less than about 1m²/g, preferably not less than about 1.5 m²/g, normaly about 1.5 toabout 4 m²/g.

The specific surface area used herein is that calculated by the BETmethod widely used in general.

From the viewpoint of convenience of utilizing as additives orexcipients of pharmaceutical preparations or food products, D-mannitolis preferably in the state of granules of crystalline aggregateespecially whose average size is about 0.05 to about 5.0 mm, morepreferably about 0.08 to about 2.0 mm in diameter. However, forms of thecrystalline aggregate is not specifically limited and any form ofcrystalline aggregate which meet the requirements and, for example,net-like or thin plate-like ones are included in the present invention,in so far as the aggregate has the above-described properties.

The αform, β form and δ form D-mannitol crystals described herein aredefined in accordance with the classification of polymorphic forms byX-ray diffraction pattern reported in Acad. Sc. Paris, t. 267 Series C,1779, (1968) by Walter-Levy, L.

The D-mannitol of the present invention can be prepared by a methodwhich comprises treating the δ form crystals employed as the startingmaterial with a water-soluble solvent and then drying the treatedmaterial, preferably, by subjecting it to rapid drying to causetransformation of the surface or inside of the starting crystals intofine β form crystals. More specifically, the method comprises a step ofmoistening the surface of the δ form crystals with a water-solublesolvent to cause successive transformation of a portion or all of the δform crystals reacted with the solvent into the β form from the surfaceto the inside, and a step of drying to suppress the growing of theresultant β form crystals. Then, normally, D-mannitol of the presentinvention exists as a mixture of δ form crystals and β form crystals.The ratio of δ form crystals and β form crystals in the mixture isdefined by the above transformation step of the crystal form and crystalgrowing step. However, it is not specifically limited.

For treating the δ form crystals with a water-soluble solvent, any meanswhich can moisten the surface of individual crystals without dissolvingcompletely in a water-soluble solvent, for example, spraying awater-soluble solvent on a thin layer of the δ form crystals oragitating while spraying or dropping a water-soluble solvent on the δform crystals, can be employed. And, in this treatment, other componentmay optionally be coexisted in so far as the surface of D-mannitolcrystals can be moistened. For example, as described in the Exampleshereinafter, treatment of a portion or of the whole mixture of aformulated end product containing D-mannitol with a water-solublesolvent also falls within the scope of this invention.

Examples of the water-soluble solvent include purified water, methanol,ethanol, acetone or a mixture thereof, and the mixing ratio is suitablychosen depending on necessity. Among them, purified water, ethanol and amixture thereof are preferably employed.

The amount of the water-soluble solvent to be used is suitably chosenaccording to a particular treatment of crystals, a particular solvent tobe used or the like, normally, from the range of about 3% to about 70%,preferably about 15% to about 40% by weight based on the weight of thestarting crystals. For example, in the case of employing a methodcomprising addition of the water-soluble solvent to the startingcrystals and agitating the mixture, preferably, the water-solublesolvent is added in an amount of about 5 w/w % or more in view of thediffusion rate of the water-soluble solvent.

In the drying step, for suppressing the growth of fine crystalsdeveloped by the above-described method, the time required for drying ispreferably as short as possible. Therefore, normally, rapid drying arepreferred in many cases. On the other hand, the starting crystals cancontinue the transition caused by treatment with the water-solublesolvent until completing the transition to the β form. Then, the dryingin the method of the present invention is determined depending on therelation with the transition rate of the crystals, thus the drying timeis not specifically limited. Therefore, for example, in the case of themethod comprising admixing the starting crystals with purified water, itis preferred to remove purified water within 48 hours, preferably 16hours, more preferably 8 hours after the crystals and purified water arehomogeneously mixed. However, the time can of course be varied with, forexample, the treatment method, solvent and drying method employed.Examples of the drying method include vacuum drying, air drying,fluidized bed drying and dielectric high frequency drying and the like,and, among them, vacuum drying is preferred.

The thus-obtained D-mannitol of the present invention has theabove-described specific surface area and exhibits an excellentcompressibility, which can be used as an excipient for directcompression, wet-granulation or dry-granulation. The mannitol can beused as a good excipient in the fields of pharmaceutical and foodproducts. It is especially useful for the production of a solidcomposition comprising a pharmacologically active component, a sweeteneror the like.

The solid composition of the present invention comprises D-mannitolhaving a special surface area of not less than about 1 m²/g. Thecomposition of the present invention further comprises, preferably, apharmacologically active component, a sweetener or the like. Thecomposition can contain a pharmacologically active component, asweetener or the like in an effective amount thereof. In particular, thecomposition of the present invention preferably comprises apharmacologically active component.

Examples of the pharmacologically active component includephysiologically active peptides, anti-tumor agents, antibiotics,antipyretics, analgesics, anti-inflammatory agents, antitussiveexpectorants, bronchodilators, sedativa, muscle relaxants,antiepileptics, antiulcer agents, antidepressant agents, antiallergicagents, cardiotanics, antiarrhythmic agents, vasodilators, hypotensivediuretics, antidiabetics, antilipidemic agents, anticoagulants,hemostatics, antituberculous agents, hormones, narcotic antagonists,bone resorption inhibitory agents, osteogenesis promoting agents,angiogenesis inhibitory agents, vitamins and the like.

Examples of the physiologically active peptides include LH-RH(luteinizing hormone releasing hormone) agonists [U.S. Pat. Nos.3,853,837, 4,008,209 and 3,972,859; British Patent No. 1,423,083;Proceedings of the National Academy of Sciences of the United States ofAmerica, 78, 6509-6512 (1981)], LH-RH antagonists (U.S. Pat. Nos.4,086,219, 4,124,577, 4,253,997, 4317,815 and 5,480,868), insulin,somatostatin, somatostatin derivatives (sandostatin, U.S. Pat. Nos.4,087,390, 4,093,574, 4,100,117 and 4,253,998), growth hormone,prolactin, adrenocorticotropic hormone (ACTH), ACTH derivatives (e.g.,ebiratide, etc.), melanocyte-stimulating hormone (MSH),thyrotropin-releasing hormone (TRH) and its derivatives (JP-A 50-121273and JP-A 52-116465), thyroid-stimulating hormone (TSH), luteinizinghormone (LH), follicle-stimulating hormone (FSH), vasopressin,vasopressin derivatives [desmopressin (Nippon Naibunpi Gakkaishi, 54, 5,676-691 (1978))], oxytocin, calcitonin, parathyroid hormone (PTH),gulcagon, gastrin, secretin, pancreozymin, cholecystokinin, angiotensin,human placental lactogen, human chorionic gonadotropin (HCG),enkephalin, enkephalin derivatives (U.S. Pat. No. 4,277,394, EP-A31567), endorphin, kyotorphin, interferons (e.g., IFN-α, β, γ, etc.)interleukins (e.g., IL-1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.),tuftsin, thymopoietin, thymosin, thymostimulin, thymichumoral factor(THF), blood thymic factor (FTS) and its derivatives (U.S. Pat. No.4,229,438) and other thymic factors [Igaku no Ayumi, 125, 10, 835-843(1983)], tumor necrosis factor (TNF), colony stimulating factors (CSF,GCSF, GMCSF, MCSF, etc.), motilin, dynorphin, bombesin, neurotensin,caerulein, bradykinin, urokinase, asparaginase, kallikrein, substance P,insulin-like growth factors (IGF-I, IGF-II), nerve growth factor (NGF),cell growth factors (EGF, TGF-α, TGF-β, PDGF, acidic FGF, basic FGF,etc.), osteogenesis factor (BMP), neurotrophic factors (NT-3, NT-4,CNTF, GDNF, BDNF, etc.), blood coagulation factors VIII and IX, lysozymechloride, polymyxin B, colistin, gramicidin, bacitracin anderythropoietin (EPO), thrombopoietin (TPO), polypeptides havingendothelin antagonistic activity (EP-A 436189, 457195 and 496452; JP-A3-94692, JP-A 3-130299) and the like.

Examples of anti-tumor agents include Bleomycin, Methotrexate,Actinomycin D, Mytomycin C, Vinblasine sulfate, Vincristine sulfate,Daunorbicin, Adriamycin, Neocarzinostatin, cytosine arabinoside,Fluorouracil, tetrahydrofuryl-5-fluorouracil, Klestin, Picibanil,Lentinan, Levamisole, Bestatin, Azimexon, Glycyrrhizin, poly I:C, polyA:U, polyICLC and the like.

Examples of antibiotics include Gentamicin, Dibekacin, Kanendomycin,Lividomycin, Tobramycin, Amikacin, Fradiomycin, Sisomicin, Tetracyclinehydrochloride, oxytetracycline hydroxchoride, Rolitetracycline,Doxycycline hydrochloride, Ampicillin, Piperacillin, Ticarcillin,Cefalotin, Cefaloridine, Cefotiam, Cefsulodin, Cefmenoxime, Cefmetazole,Cefazolin, Cefotaxime, Cefoperazone, Ceftizoxime, Moxalactam,Thienamycin, Sulfazecin, Azthreonam, Cefotiam hexetil hydrochloride,acetoxymethyl (+)-(5R,6S)-6-[(R)-1-hydroxyethyl]-7-oxo-3-(3-pyridyl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylateand the like.

Examples of antipyretics, analgesics and anti-inflammatory agentsinclude salicylic acid, sulpyrine, flufenamic acid, diclofenac,indomethacin, morphine, pethidine hydrochloride, levorphanol tartrate,oxymorphone and the like.

Examples of antitussive expectorants include ephedrine hydrochloride,methylephedrine hydrochloride, noscapine hydrochloride, codeinephosphate, dihydrocodeine phosphate, alloclamide hydrochloride,clofedanol hydrochloride, picoperidamine hydrochloride, cloperastine,protokylol hydrochloride, isoproterenol hydrochloride, salbutamolsulfate, terbutaline sulfate and the like.

Examples of bronchodilators include phenyl-propanolamine hydrochloride,theophylline, salbutamol sulfate and the like.

Examples of sedativa include chlorpromazine, prochlorperazine,trifluoperazine, atropine sulfate, methylscopolamine bromide and thelike.

Examples of muscle relaxants include pridinol methansulfonate,tubocurarine chloride, pancuronium bromide and the like.

Examples of antiepileptics include phenytoin, ethosuximide,acetazolamide sodium, chlordiazepoxide and the like.

Examples of antiulcer agents include benzimidazole compounds (U.S. Pat.Nos. 4,045,563, 4,255,431 and 4,472,409; EP-A 45200, 5129, 174726,175464 and 208452; GB-A 2134523), metoclopramide, histidinehydrochloride and the like.

Examples of antidepressant agents include imipramine, clomipramine,noxiptiline, phenelzine sulfate and the like.

Examples of antiallergic agents include diphenhydramine hydrochloride,chlorpheniramine maleate, tripelennamine hydrochloride, methdilazinehydrochloride, clemizole hydrochloride, diphenylpyraline hydrochloride,methoxyphenamine hydrochloride and the like.

Examples of cardiotonics include trans-π-oxocamphor, theophyllol,aminophylline, etilefrin hydrochloride and the like.

Examples of antiarrhythmic agents include propranolol, alprenolol,bufetolol, oxprenolol and the like.

Examples of vasodilators include oxyfedrine hydrochloride, diltiazem,tolazoline hydrochloride, hexobendine, bamethan sulfate and the like.

Examples of hypotensive diuretics include hexamethonium bromide,pentrinium, mecamylamine hydrochloride, ecarazine hydrochloride,clonidine and the like.

Examples of antidiabetics include insulin senstivity enhancer (EP-A749751), voglibose, miglitol, glymidine sodium, glipizide, phenforminhydrochloride, buformin hydrochloride, metformin and the like.

Examples of antilipidemic agents include sodium3R,5S-(+)-erythro-(E)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-methoxymethyl-pyrid-3-yl]-3,5-dihydroxy-hept-6-enoate,pravastatin sodium, simvastatin, clinofibrate, clofibrate, simfibrate,bezafibrate and the like.

Examples of anticoagulants include heparin sodium and the like.

Examples of hemostatics include thromboplastin, thrombin, menadionsodium bisulfite, acetomenaphtone, ε-aminocaproic acid, tranexamic acid,carbazochrome sodium sulfonate, adrenochrome monoaminoguanidinemethanesulfonate and the like.

Examples of antituberculous agents include isoniazid, ethambutol,para-aminosalicylic acid and the like.

Examples of hormones include prednisolone, prednisolone sodiumphosphate, dexamethasone sodium sulfate, betamethasone sodium phosphate,hexoestrol phosphate, hexoestrol acetate, methimazole and the like.

Examples of narcotic antagonists include levallorphan tartrate,nalorphine hydrochloride, naloxone hydrochloride and the like.

Examples of bone resorption inhibitory agents include ipriflavone andthe like.

Examples of osteogenesis promoting agents include polypeptides such asBMP, PTH, TGF-β, IGF-1 and the like,(2R,4S)-(−)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepine-2-carboxamide,2-(3-piridyl) -ethane-1, 1-diphosphonic acid and the like.

Examples of angiogenesis inhibitory agents include angiogenesisinhibitory steroids [Science, 221, 719 (1983)], fumagillin (EP-A325199), fumagillol derivatives (EP-A 357061, 359036, 386667 and 415294)and the like.

Examples of vitamins include cyanocobalamine, thiamine, ascorbic acid,pantothenic acid and the like.

The above-described pharmacologically active components may be in theform of pharmaceutically acceptable salts. Examples of such saltsinclude salts with inorganic acids (e.g., hydrochloric acid, sulfuricacid, nitric acid, etc.), organic acids (e.g., carbonic acid, bicarbonicacid, succinic acid, acetic acid, propionic acid, trifluoroacetic acid,etc.), inorganic bases (e.g., alkali metals such as sodium, potassium,etc. and alkaline earth metals such as calcium, magnesium, etc.) andorganic bases (organic amines such as triethylamine, etc. and basicamino acids such as arginine, etc.).

Among the above-described pharmacologically active components, thosehaving high moisture-sensitivity are apt to show changes in theirproperties during the production of pharmaceutical preparations byconventional pharmaceutical technique and are difficult to handle. Thepresent invention is applicable to even such high moisture-sensitivecomponents and provides a novel method for producing pharmaceuticalpreparations of such high moisture-sensitive pharmacologically activecomponents.

The term “high moisture-sensitive component” means a component whichundergoes chemical changes (decomposition, coloring and the like) orphysiological changes (change of crystalline form and the like) due tothe presence of water.

The pharmacologically active components are preferably physiologicallyactive peptides, antibiotics, bronchodilators, antilipidemic agents andvitamins. More preferably, the pharmacologically active component isantilipidemic agents, in particular, sodium3R,5S-(+)-erythro-(E)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-methoxymethylpyrid-3-yl]-3, 5-dihydroxy-hept-6-enoate.

Examples of the sweeteners include starch sugar, reduced maltose,sorbitol, sucrose, fructose, lactose, honey, xylitol, saccharin,glycyrriza and its extracts, glycyrrhetic acid, hydrangea tea, aspartameand the like. Among them, aspartame which is a high moisture-sensitivecomponent is preferred.

In addition to the above D-mannitol and components, the solidcomposition of the present invention may further contain any otherexcipients, disintegrators, binders, glidants, lubricants or the like,which are commonly employed for the preparation of food products ormedicaments. Examples of such excipients include lactose, starch,sucrose, crystalline cellulose, anhydrous calcium hydrogenphosphate andcalcium carbonate. Disintegrators are, for example, low-substitutedhydroxypropylmethylcellulose, carboxymethylcellulose,carboxymethylcellulose calcium, carmellose, closcarmellose sodium,carboxymethyl starch sodium, partial pregeratinized starch andcrospovidone. Binders are, for example, methylcellulose,hydroxypropylcellulose, hydroxypropyl methylcellulose,carboxymethylcellulose sodium, pregeratinized starch, acacia, agar,gelatine, tragacanth, sodium alginate, polyvinyl pyrrolidone andpolyvinyl alcohol. Glidants are, for example, hydrated silicon dioxide,light anhydrous silicic acid, synthetic aluminum silicate, synthetichydrotalcite, dried aluminum hydroxide gel, kaolin, calcium silicate andmagnesium metasilicate aluminate. Lubricants are, for example, magnesiumstearate, calcium stearate, stearic acid, talc, sodium lauryl sulfate,hydrogenated vegetable oil, microcrystalline wax, sucrose fatty acidester and polyethylene glycol.

While the solid composition of the present invention can be produced byper se known technique, the D-mannitol of the present invention may beemployed in the production step in αform prepared in advance, or may beadded in the form of starting crystals to allow them to be transformedinto the desired crystal shape during the production process ofpharmaceutical preparations and food products.

Since the D-mannitol of the present invention, which has an increasedbinding points due to microcrystallization of the primary particleswhile retaining the inherent chemical and biological properties, hasexcellent compatibility and compressibility, it is remarkably useful asan excipient. According to the method of the present invention,D-mannitol can be prepared conveniently and safely. Thus, the presentinvention contributes a great deal to the design of novel pharmaceuticalpreparations and food products and to the development of pharmaceuticalmanufacturing and food manufacturing techniques.

The following comparative examples and examples further illustrate thepresent invention, but they do not limit the scope of the presentinvention.

In the comparative examples and examples, the β form and δ formD-mannitol crystals were prepared by substantially the same manner asdescribed in MICROSCOPE, 18, 279-285 (1970).

COMPARATIVE EXAMPLE 1

To 100 g of the β form D-mannitol crystals was added 20 g of purifiedwater. The mixture was stirred in a mortar for 3 minutes to moisten thecrystals evenly, which was subjected to vacuum drying (40° C., 16hours), followed by pulverizing through a sieve of No. 16 mesh. Theparticles thus obtained (specific surface area: 0.5 m²/g) were subjectedto compression under the following conditions.

Compressing machine: Autograph (Shimadz Seisakusho Ltd.)

Compression rate: 10 mm/min.

Punch: 10 mmφ, flat

Weight: 400, mg

COMPARATIVE EXAMPLE 2

In a agitating granulator (Powrex, Vertical Granulator VG10 type), 1500g of the β form D-mannitol crystals was evenly moistened with 375 g ofpurified water (200 rpm, 2 minutes), which was subjected to vacuumdrying (40° C., 16 hours), followed by milling in a power mill (ShowaKagaku, P-3 type punching size: 1.5 mmφ). The powder thus obtained(specific surface area: 0.5 m²/g; hereinafter called “β form crystalsAG”) was mixed as in the following formula and subjected to tablettingunder the following conditions.

Formula: β form crystals AG 709.2 g phenylpropanolamine hydrochloride 78.8 g magnesium stearate  12.0 g Total 800.0 g Tabletting machine:Correct 19 AWC (Kikusui Seisakusho) Tabletting pressure: 1200-2400kg/cm² Rotational frequency: 30 rpm punch: 8.0 mmφ, flat facebeveled-edge Weight: 180 mg

COMPARATIVE EXAMPLE 3

In a agitating granulator (Powrex, Vertical Granulator VG 10 type), amixture of 1267.2 g of the β form D-mannitol crystals and 316.8 g ofphenylpropanolamine hydrochloride was evenly moistened with 240 g ofpurified water (200 rpm, 2 minutes), which was subjected to vacuumdrying (40° C., 16 hours), followed by milling in power mill (ShowaKagaku, P-3 type, punching size: 1.5 mmφ). A mixture of 792.0 g ofthus-obtained powders and 8.0 g of magnesium stearate was subjected totabletting under the following conditions.

Tabletting machine: Correct 19 AWC (Kikusui Seisakusho)

Tabletting pressure: 100-3000 kg/cm

Rotational frequency: 30 rpm

Punch: 8.0 mmφ, flat-face beveled-edge

Weight: 180 mg

COMPARATIVE EXAMPLE 4

In a agitating granulator (Powrex, Vertical Granulator VG 10 type), 1500g of the β form D-mannitol crystals was evenly moistened with 375 g ofpurified water (200 rpm, 2 minutes), which was subjected to vacuumdrying (40° C., 16 hours), followed by milling in power mill (showaKagaku, P-3 type, punching size: 1.5 mmφ). The β form crystals AG(specific surface area: 0.5 m²/g) was mixed as in the following formulaand subjected to dry granulating. The slugs thus obtained were milled inpower mill (Showa Kagaku, P-3 type, punching size: 2.0 mmφ).

Formula: β form crystals AG 709.2 g phenylpropanolamine hydrochloride 78.8 g magnesium stearate  12.0 g Total 800.0 g Machine: Rollercompactor (FREUND, Model-mini) Rotational frequency: 3 rpmpowder-feeding rate: 20 rpm Compression pressure: 50 kg/cm² Thickness offlakes: about 2.0 mm

EXAMPLE 1

To 100 g of the δ form D-mannitol crystals was added 20 g of purifiedwater. The mixture was stirred in a mortar for 3 minutes to moisten thecrystals evenly, which was subjected to vacuum drying (40° C., 16hours), followed by pulverizing through a sieve of 16 mesh. The powdersthus obtained (specific surface area: 1.9 m²/g) were subjected tocompression molding under the same conditions as in ComparativeExample 1. On the other hand, as comparative compressed products,compressed products were prepared respectively using untreated δ formD-mannitol crystals (specific surface area: 0.7 m²/g) and 0 formD-mannitol crystals (specific surface area: 0.5 m²/g) in substantiallythe same manner. The hardness of the compressed product thus obtainedand that of the compressed product in Comparative Example 1 weredetermined by an instrument of measuring tablet fracture strength(Toyama Sangyo). As the result, no difference of hardness wasrecognized, under the above-described compression conditions, among thethree compressed products using untreated δ form crystals, untreated 5form crystals and treated D form crystals (Comparative Example 1). Thehardness of the compressed product prepared in this Example 1 was foundto be remarkably high as compared with the compressed product preparedby using untreated δ form crystals or treated 5 form crystals (FIG. 1).And, the D-mannitol of this Example 1 was, by observation under ascanning electron microscope, unlike the starting crystals (FIG. 3),porous particle consisting of fine-crystalline aggregates of D-mannitol(FIG. 2), whose powder X-ray diffraction spectrum was measured toconfirm the transformation of δ form to 0 form (FIG. 4).

EXAMPLE 2

In a agitating granulator (Powrex, Vertical Granulator VG10 type), 1500g of the δ form D-mannitol crystals was evenly moistened with 375 g ofpurified water (200 rpm, 2 minutes), which was subjected to vacuumdrying (40° C., 16 hours), followed by milling in power mill (ShowaKagaku, P-3 type punching size: 1.5 mmφ). The powder thus obtained(specific surface area: 1.9 m²/g; hereinafter called “δ form crystalsAG”) was mixed as in the following formula and subjected to tabletting.The hardness of the compressed product thus obtained and that of thecompressed product of the Comparative Example 2 were determined by aninstrument of measuring tablet fracture strength (Toyama Sangyo). Theresults showed that the compressed product of this Example 2 showedremarkably excellent compressibility and gave sufficient hardness with alow tabletting pressure, while the compressed product of ComparativeExample 2 showed poor compressibility and capping occurred with atabletting pressure of 1800 kg/cm² or more to give no satisfactorytablets (FIG. 5).

Formula: δ form crystals AG 709.2 g phenylpropanolamine hydrochloride 78.8 g magnesium stearate  12.0 g Total 800.0 g Tabletting machine:Correct 19 AWC (Kikusui Seisakusho) Tabletting pressure: 600-1800 kg/cm²Rotational frequency: 30 rpm punch: 8.0 mmφ, flat-face beveled-edgeWeight: 180 mg

EXAMPLE 3

In an agitating granulator (Powrex, Vertical Granulator VG 10 type), amixture of 1267.2 g of the δ form D-mannitol crystals and 316.8 g ofphenylpropanolamine hydrochloride was evenly moistened with 240 g ofpurified water (200 rpm, 2 minutes), which was subjected to vacuumdrying (40° C., 16 hours), followed by milling in power mill (ShowaKagaku, P-3 type, punching size: 1.5 mmφ). A mixture of 792.0 g ofthus-obtained powders and 8.0 g of magnesium stearate was subjected totabletting under the following conditions. The hardness of thecompressed product was determined by an instrument of measuring tabletfracture strength (Toyama Sangyo). As a result, the compressed productof this Example 3 showed remarkably excellent compressibility and gavesufficient hardness, while the compressed product of Comparative Example3 which was prepared by using β form D-mannitol crystals showed poorcompressibility and capping was occurred with a tabletting pressure of2000 kg/cm² or more to give no satisfactory tablets (FIG. 6).

Tabletting machine: Correct 19 AWC (Kikusui Seisakusho)

Tabletting Pressure: 1000-3000 kg/cm²

Rotational frequency: 30 rpm

Punch: 8.0 mm+, flat-face beveled-edge

Weight: 180 mg

EXAMPLE 4

In an agitating granulator (Powrex, Vertical Granulator VG 10 type),1500 g of the δ form D-mannitol crystals was evenly moistened with 375 gof purified water (200 rpm, 2 minutes), which was subjected to vacuumdrying (40° C., 16 hours), followed by milling in power mill (ShowaKagaku, P-3 type, punching size: 1.5 mmφ). The δ form crystals AG thusobtained (specific surface area: 1.9 m²/g) was mixed as in the followingformula and subjecting to dry granulating under the same conditions asin Comparative Example 4. The slugs thus obtained were milled in powermill (Showa Kagaku, P-3 type, punching size: 2.0 mmφ). The strength ofthe granules was determined by an instrument measuring granular strength(Okada Seiko, Grano), and the results were shown in (FIG. 7), from whichthe average granular strength of the both products was calculated (n=30;1.0-2.0 mm) to find that the average granular strength of the granulesof this Example 4 was 601.7 g, while that of the granules of ComparativeExample 4 was 292.0 g.

As is clear from the results, the formula in this Example 4 using the δform crystals AG gave hard granules containing little micropowders andshowed excellent properties for filling in capsules. On the other hands,since the strength of the granules obtained by the formula inComparative Example 4 using β form crystals AG was not sufficient,encapsulation of them was difficult.

Formula: δ form crystals AG 709.2 g phenylpropanolamine hydrochloride 78.8 g magnesium stearate  12.0 g Total 800.0 g

EXAMPLE 5

To agitating granulators (Powrex, Vertical Granulator VG 10 type) eachcontaining 1000 g of δ form D-mannitol crystals, 50, 100, 150, 200, 250and 300 g of purified water (5-30 w/w % based on the weight of mannitol)were respectively added en bloc. The respective mixtures were agitated(2 minutes, 200 rpm), followed by vacuum drying (40° C., 16 hours). Eachdried material was milled in power mill (Showa Kagaku, P-3 type,punching size: 1.5 mmφ). The thus obtained powder (specific surfaceareas: 1.0, 1.4, 1.7, 1.9, 3.5 and 2.7 m²/g, respectively) was subjectedto tabletting under the following conditions. The hardness of thecompressed product was determined by an instrument of measuring tabletfracture strength (Toyama Sangyo). The specific surface area of thepowders was measured by BET method. The results showed that the volumeof water used for the treatment gave an influence on the specificsurface area of the product obtained by treatment of the crystals tocorrespondingly influence on the hardness of the compressed product(FIG. 8). In FIG. 8, numerical values in the parentheses show % byweight of the purified water used relative to the weight of δ formD-mannitol crystals.

Tabletting machine: Correct 19 AWC (Kikusui Seisakusho)

Tabletting pressure: 2000 kg/cm²

Rotational frequency: 30 rpm

Punch: 8.0 mmφ, flat-face beveled-edge

Weight: 180 mg

EXAMPLE 6

5.043 kg of δ form D-mannitol was treated in a high shear mixer (LoedigeMGT-30) with a granulation liquid comprising of 6 g of sodium3R,5S-(+)-erythro-(E)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-methoxymethyl-pyrid-3-yl]-3,5-dihydroxy-hept-6-enoate(cerivastatin), 108 g of polyvinyl pyrrolidone (polyvidone 25) and 420 gof purified water. The wet granulation mass was rasped and then dried ina fluidized bed dryer (inlet air temperature 60-80° C.) until a residualmoisture content of preferably 1.5% or less was reached. The granuleswere sieved (oscillation sieve, 0.8 mm) and then blended with 162 g ofcrospovidone and 81 g of magnesium stearate. Compression of thegranulates under the following conditions resulted in tablets withfavorable hardness.

Tabletting machine: Kilian T 200

Compression force: 6-8 kN

Punch size: 6 mm diameter

9 mm radius of curvature

Tablet weight: 90 mg

What is claimed is:
 1. A process for preparing a D-mannitol said processcomprising moistening the surface of δ form D-mannitol crystals with awater-soluble solvent without dissolving the δ form D-mannitol crystalscompletely in the water-soluble solvent, followed by drying themoistened δ form D-mannitol crystals to obtain the D-mannitol, saidwater-soluble solvent being in an amount of about 3 to about 70 W/W %based on the weight of the δ form D-mannitol crystals, said D-mannitol(a) being in the 5 form crvstals alone or a mixture of the β formcrystals with the δ form crystals and (b) having a specific surface areaof not less than about 1 m²/g.
 2. A D-mannitol, which is the P formcrystals alone or a mixture of the β form crystals with the δ formcrystals, said D-mannitol having a specific surface area of not lessthan about 1 m²/g and being produced by a process which comprisesmoistening the surface of δ form D-mannitol crystals with awater-soluble solvent without dissolving the δ form D-mannitol crystalscompletely in the water-soluble solvent, followed by drying themoistened δ form D-mannitol crystals to obtain the D-mannitol.
 3. Aprocess for preparing a D-mannitol, said process comprising moisteningthe surface of δ form D-mannitol crystals with a water-soluble solventwithout dissolving the δ form D-mannitol crystals completely in thewater-soluble solvent, followed by drying the moistened δ formD-mannitol crystals to obtain the D-mannitol, said D-mannitol (a) beingin the β form crystals alone or a mixture of the P form crystals withthe δ form crystals and (b) having a specific surface area of not lessthan about 1 m²/g.